We propose to continue and extend our cellular neurophysiological studies by focussing on separate opioid-containing circuits within a major limbic network containing several loci of prodynorphin- and proenkephalin-derived peptides. We shall apply extracellular and intracellular recording techniques, both in vivo and in vitro, to selected portions of the entorhinal cortical-dentate-hippocampal-accumbens system, since work in our laboratory and others implicates these areas as important in self-stimulation and opiate-seeking behavior. The objectives of these studies will be to attempt to determine whether the opioid peptides within specific circuits of this system function as neurotransmitters, whether their are cellular correlates of opiate seeking behavior and whether the opioid peptides and relevant opiate receptors in this system are involved in such behavior. We shall pursue the first and third objectives in vivo by administering opiates, opioid peptides and specific opiate receptor antagonists by local iontophoresis and micropneumatic methods, and by the i.v. or i.p. systemic route. In vitro we will use superfusion of these substances and the same local application methods as in vivo. Endogenous opioids will be released in vivo and in vitro by electrode stimulation of opioid-containing pathways. Single-electrode voltage clamp methods will be used for analysis of the more covert voltage-dependent opioid effects. We shall record single units in nucleus accumbens in awake animals involved in a heroin self-administerion protocol, to seek cellular correlates of opiate reward phenomena. For the final goal, we will examine responsivity of neurons in this system to the opioid peptides after chronic treatment with morphine, in order to compare the naive state to that of the heroine-seeking state. We believe these studies will help unravel the role of the opioid peptides and their receptors in normal, opiate-seeking and opiate addictive behavior.